Retro-inverso peptide inhibitor nanoparticles as potent inhibitors of aggregation of the Alzheimer's Aβ peptide.

Aggregation of amyloid-β peptide (Aβ) is a key event in the pathogenesis of Alzheimer's disease (AD). We investigated the effects of nanoliposomes decorated with the retro-inverso peptide RI-OR2-TAT (Ac-rGffvlkGrrrrqrrkkrGy-NH) on the aggregation and toxicity of Aβ. Remarkably low concentrations of these peptide inhibitor nanoparticles (PINPs) were required to inhibit the formation of Aβ oligomers and fibrils in vitro, with 50% inhibition occurring at a molar ratio of ~1:2000 of liposome-bound RI-OR2-TAT to Aβ.

β-amyloid fibrils in Alzheimer disease are not inert when bound to copper ions but can degrade hydrogen peroxide and generate reactive oxygen species.

According to the "amyloid cascade" hypothesis of Alzheimer disease, the formation of Aβ fibrils and senile plaques in the brain initiates a cascade of events leading to the formation of neurofibrillary tangles, neurodegeneration, and the symptom of dementia. Recently, however, emphasis has shifted away from amyloid fibrils as the predominant toxic form of Aβ toward smaller aggregates, referred to as "soluble oligomers." These oligomers have become one of the prime suspects for involvement in the early oxidative damage that is evident in this disease.

Ultrasonic force microscopy for nanomechanical characterization of early and late-stage amyloid-β peptide aggregation.

The aggregation of amyloid-β peptides into protein fibres is one of the main neuropathological features of Alzheimer's disease (AD). While imaging of amyloid-β aggregate morphology in vitro is extremely important for understanding AD pathology and in the development of aggregation inhibitors, unfortunately, potentially highly toxic, early aggregates are difficult to observe by current electron microscopy and atomic force microscopy (AFM) methods, due to low contrast and variability of peptide attachment to the substrate. Here, we use a poly-L-Lysine (PLL) surface that captures all protein components from monomers to fully formed fibres, followed by nanomechanical mapping via ultrasonic force microscopy (UFM), which marries high spatial resolution and nanomechanical contrast with the non-destructive nature of tapping mode AFM.